The present invention relates to the use of viscoelastics, typically in surgery, to prevent or reduce unwanted tissue adhesion and/or fibrosis subsequent to the trauma or surgical insult. The methods of the present invention are particularly useful in the field of otic therapy, and especially in therapies associated with the treatment of middle ear conditions which arise as a consequence of disease, injury, surgery and the like. The compositions and methods of the present invention are particularly useful in mastoidectomy and tympanoplasty surgeries. In addition, the compositions of the present invention may be used as a packing agent, with or without a therapeutic agent, for the management of otitis external in the external ear canal.
The human ear consists of a series of three compartments: the external, middle and inner ears. These are grossly depicted in FIG. 1. The external ear, which consists of the cartilaginous outer ear and the external canal are designed to gather sound and protect the tympanic membrane, which marks the beginning of the middle ear. The middle ear is an air filled compartment having three principle structures: (1) the tympanic membrane; (2) the ossicular chain (consisting of the incus, malleus, and stapes); and (3) the eustachian tube. The tympanic membrane and ossicular chain function to convert sound waves passing through the external cannel into mechanical vibrations which can then be processed by the inner ear. The eustachian tube functions as a pressure equalizer to avoid undue strain on the tympanic membrane. The inner ear consists of the cochlea and the vestibular apparatus. The xe2x80x9csnail shellxe2x80x9d shaped cochlea contains sound receptor cells, which respond to the sound vibrations and send signals to the brain. It is these signals that are responsible for the sound being xe2x80x9cheard.xe2x80x9d The vestibular apparatus of the inner ear operates in a similar fashion, but deals with balance and motion, rather than sound.
Of the three ear compartments, the middle ear is perhaps the most prone to trauma which can result in loss of hearing. One reason for this is that the tympanic membrane and the ossicular chain are extremely delicate. Any trauma which impedes or alters the motility of the respective components will necessarily impact the transducer function they serve. The three tiny bones of the ossicular chain and reconstructions thereof are particularly susceptible to impaired function if the ossicular chain is permitted to collapse before it is sufficiently healed. Such collapse can result in undesirable adhesions and fibrosis that can severely limit the motility of the ossicular chain members and hence their ability to serve the transducer function. In order to stabilize the tympanic membrane and the ossicular chain, at the end of middle ear surgery, the middle ear compartment is typically xe2x80x9cpackedxe2x80x9d with some type of gel product.
Several such products are known. Absorbable gelatin sponge (AGS) (Gelfoam(trademark)) with or without Gelfilm(trademark)xe2x80x94(both of Pharmacia Corp., Kalamazoo, Mich., U.S.A.) have been used as supportive aids in the middle ear. One drawback to the use of these products is the relatively difficult xe2x80x9ccut to fitxe2x80x9d technique that must be employed by the surgeon to effect the packing. Also, although used extensively in middle ear surgery, AGS has been implicated as a possible factor in the development of unexpected adhesions and new bone formation. Other attempts have been made to improve the supportive properties of these packing materials. Hyaluronic acid (A) foam (Genzyme Corporation, Cambridge, Mass., U.S.A.) has also been tested, but has shown only marginal benefits over conventional packing. Krupala et al., Am J Otol 19:546-550 (1998). xe2x80x9cThe degree of adhesion was similar for both groups [AGS and HA foam].xe2x80x9d Id. at 549. Rapid elimination of conventional HA solutions through the Eustachian tube may limit its capability to provide adequate graft support, leading to adhesion formation. Laurent et al., Hyaluronic acid reduces connective tissue formation in middle ears filled with absorbable gelatin sponge, Am. J. Otolaryogol., 7(3):181-186 (1986). Krupata et al. have suggested that such elimination can be avoided by plugging the eustachian tube with gelatin sponge. Id. at 546. This approach, however, appears not to be ideal as it requires two separate packing materials.
Merchant et al., Current status and future challenges of tympanoplasty, Eur Arch Otorhinolaryngol, 255:221-228 (1998), discuss the deficiencies of currently available therapies in terms of middle ear adhesions and fibrosis:
Proliferation of fibrous tissue and the formation of adhesions are significant problems that are more prone to occur when the middle ear mucosa is diseased, removed, or traumatized. Many different materials have been placed in the middle ear in an attempt to prevent formation of adhesions and fibrous tissue. These materials include absorbable gelatin sponge (Gelfoam), hyaluronic acid. Silastic and Teflon, Gelfoam elicits a host inflammatory response leading to its resorption [citations omitted]. In some cases, this inflammatory response results in adhesions, especially when the middle ear mucosa is deficient. Further, gelfoam is resorbed within 2 weeks, which is probably insufficient time for mucosal regeneration to occur. Hyaluronic acid is somewhat more difficult to handle than gelfoam [citation omitted] and is also absorbed before mucosal regeneration is likely to be completed. Silastic and Teflon sheeting are relatively inert [citations omitted] but they are not resorbed and can extrude on occasion. In some cases, Silastic and Teflon become engulfed by fibrous tissue leading to a nonaerated ear [citation omitted]. Hence, none of the currently available spacer materials is ideal. What is needed is a material that will remain in place for several weeks to allow sufficient time for mucosal regeneration and will then undergo degradation and resorption so that the ear can become aerated without fibrosis.
Surgical grade viscoelastics are known in the art. Several ophthalmic viscoelasltics are commercially available: VISCOAT(copyright), PROVISC(copyright), CELLUGEL(copyright) and DUOVISC(copyright) (Alcon Laboratories, Inc., Fort Worth, Tex., U.S.A.); HEALON(copyright) and HEALON GV(copyright) (Pharmacia Corp., Kalamazoo, Mich., U.S.A.); OCUCOAT(copyright), AMVISC(copyright), and AMVISC(copyright) PLUS (Bausch and Lomb Surgical, Claremont, Calif., U.S.A.); and VITRAX(copyright) (Allergan, Irvine, Calif., U.S.A.).
It is also known that certain viscoelastics may serve as carriers or drug delivery devices for pharmacologically active substances. See, e.g. U.S. Pat. No. 5,166,331. Kelly et al., In vitro release kinetics of gentamycin from a sodium hyaluronate gel delivery system suitable for the treatment of peripheral vestibular disease, Drug Dev. Indust. Pharm. 25(1):15-20 (1999), disclose in vitro testing of a delivery system comprising gentamycin in a sodium hyaluronate gel for the treatment of peripheral vestibular disease. World Patent No. WO 98/41171 entitled xe2x80x9cControlled Release of Pharmaceuticals in the Anterior Chamber of the Eyexe2x80x9d relates to compositions which maintain structural integrity of the anterior chamber of the eye during ophthalmic surgery and thereby protect anterior segment tissues while providing sustained delivery of drugs (e.g., miotics, mydriotics or anesthetics). The ocular surgical use of viscoelastic agents having different cohesive properties is disclosed in U.S. Pat. No. 5,273,056. Prior art viscoelastics, however, are not known to be particularly well-suited for use as a middle ear packing material, for the aforementioned reasons.